Complete response of metastatic microsatellite-stable BRAF V600E colorectal cancer to first-line oxaliplatin-based chemotherapy and immune checkpoint blockade

Oncoimmunology. 2024 Jun 28;13(1):2372886. doi: 10.1080/2162402X.2024.2372886. eCollection 2024.

Abstract

The randomized METIMMOX trial (NCT03388190) examined if patients with previously untreated, unresectable abdominal metastases from microsatellite-stable (MSS) colorectal cancer (CRC) might benefit from potentially immunogenic, short-course oxaliplatin-based chemotherapy alternating with immune checkpoint blockade (ICB). Three of 38 patients assigned to this experimental treatment had metastases from BRAF-mutant MSS-CRC, in general a poor-prognostic subgroup explored here. The ≥70-year-old females presented with ascending colon adenocarcinomas with intermediate tumor mutational burden (6.2-11.8 mutations per megabase). All experienced early disappearance of the primary tumor followed by complete response of all overt metastatic disease, resulting in progression-free survival as long as 20-35 months. However, they encountered recurrence at previously unaffected sites and ultimately sanctuary organs, or as intrahepatic tumor evolution reflected in the terminal loss of initially induced T-cell clonality in liver metastases. Yet, the remarkable first-line responses to short-course oxaliplatin-based chemotherapy alternating with ICB may offer a novel therapeutic option to a particularly hard-to-treat MSS-CRC subgroup.

Keywords: BRAF mutation; T-cell receptor; colorectal cancer; immune checkpoint blockade; metastasis; microsatellite-stable; oxaliplatin.

Publication types

  • Case Reports
  • Randomized Controlled Trial

MeSH terms

  • Aged
  • Aged, 80 and over
  • Antineoplastic Combined Chemotherapy Protocols* / therapeutic use
  • Colorectal Neoplasms* / drug therapy
  • Colorectal Neoplasms* / genetics
  • Colorectal Neoplasms* / pathology
  • Female
  • Humans
  • Immune Checkpoint Inhibitors* / pharmacology
  • Immune Checkpoint Inhibitors* / therapeutic use
  • Microsatellite Instability / drug effects
  • Mutation
  • Oxaliplatin* / administration & dosage
  • Oxaliplatin* / therapeutic use
  • Proto-Oncogene Proteins B-raf* / antagonists & inhibitors
  • Proto-Oncogene Proteins B-raf* / genetics
  • Treatment Outcome

Substances

  • Oxaliplatin
  • Proto-Oncogene Proteins B-raf
  • Immune Checkpoint Inhibitors
  • BRAF protein, human

Grants and funding

This work was supported by the Norwegian Cancer Society under grant 182496; the South-Eastern Norway Regional Health Authority under Grants 2018054, 276940, and 2018014; and Bristol-Myers Squibb (by providing nivolumab free of charge and an associated research grant). This was an investigator-initiated trial and, hence, the funders had no role in the design and conduct of the study, the collection, management, analysis, and interpretation of the data, the preparation, review, or approval of the manuscript, or the decision to submit the manuscript for publication. Bristol-Myers Squibb reviewed the manuscript for possible intellectual property content before submission for publication.